Method of treating and preventing neuro-olfactory triggered or aggravated illnesses or related conditions

ABSTRACT

A composition for use in a nasal application, the composition including an aqueous carrier and a viscosity agent. The viscosity agent is in the range of about 4% to about 15% by weight. The viscosity agent is in solution with the aqueous carrier. The solution of the aqueous carrier and the viscosity agent is configured as a thixotropic composition.

This application is a divisional of U.S. patent application Ser. No.15/494,643, which application is a continuation-in-part of U.S. patentapplication Ser. No. 13/263,038 filed Oct. 5, 2011, which applicationclaims priority to PCT Patent Application Serial No. PCT/US10/30097filed Apr. 6, 2010, which claims priority to U.S. Provisional PatentApplication Ser. No. 61/167,005 filed Apr. 6, 2009, all of which arehereby incorporated by reference.

BACKGROUND OF THE INVENTION 1. Technical Field

This invention relates to methods of treating neuro-olfactory triggeredor related or exacerbated conditions in general, and to methods oftemporarily and safely disabling and/or inhibiting a subject's sense ofsmell in particular.

2. Background Information

Many physical conditions are known to be triggered or caused in whole,or in part, or aggravated by a neuro-olfactory response to an odorant orirritant chemical (hereinafter referred to as an odorant or an odor), orchemicals sensed by the olfactory receptors of a subject. Suchconditions (sometimes referred to as “disorders”) can include one ormore of multiple chemical sensitivity, somatoform disorder, chronicfatigue syndrome, fibromyalgia, panic disorder, autism, epilepsy, asthmaand post-traumatic stress disorder in which afflicted individuals havemay hypersensitivity to chemical odorants. For instance, panic attackshave been shown to be triggered by certain odorants in susceptibleindividuals. Over-eating habits that lead to obesity also have acomplex, not yet completely understood, neuro-olfactory components.

Multiple Chemical Sensitivity (MCS) is one example of a disorder, orconstellation of disorders, that causes certain individuals to havemulti-organ symptoms in response to low-level chemical exposures thatare considered safe for the general population. Individuals with MCS mayexperience a large catalogue of debilitating symptoms after an exposureto certain chemical substances. Examples of debilitating symptomsinclude the following: a) neurologic symptoms including headache,fatigue, irritability, cognitive dysfunction, decreased attention span,loss of concentration and memory, dizziness, loss of motivation,confusion, sleep disturbances, anxiety, depression, mood swings,neurasthenia, numbness, hyperactivity, shortness of breath,tingling/numbness in fingers/toes; b) cardiovascular symptoms includingpalpitations, irregular heartbeat, etc.; c) respiratory symptomsincluding dyspnea, cough, chest pain and tightness, shortness of breath,rhinorrhea, nasal and eye burning, pharyngeal irritation; d)gastrointestinal symptoms include dyspepsia, diarrhea, nausea; e)genitourinary symptoms including dysmenorrhea, urinary frequency,ovarian cysts; f) musculoskeletal symptoms including myalgia, weakness,muscle tension, arthralgia, dyskinesia; and g) dermatologic symptomsincluding skin irritation.

The degree of sensitivity to each odorant or irritant chemical varieswith each individual with MCS, but a general, but non-comprehensive,list of problem odorants and irritant chemicals that includes: solvents,pesticides, combustion products of gas, oil, and coal, fresh paint,turpentine, mineral spirits, fertilizers, perfumes, cosmetics, nailpolish, cleaning products, air fresheners, cigarette smoke, carpet,adhesives, building materials, automobile and diesel exhaust, roof androad tar, industrial air pollutants, chemical preservatives (sulfur,sweetening agents), chlorine in water, medications, synthetic textiles,copy machines, and laser printers. The prevalence of this disorder inthe United States is believed to be between 0.2% and 6% of thepopulation, with 4% being an often-cited figure. In one study,Silberschmidt reports that thirty percent (30%) of all Swedishhousepainters were shown to have MCS. Approximately thirty percent (30%)of the entire population experiences some low-level, but oftendebilitating, response to aggravating chemicals.

While the etiology of MCS is not known, it is generally felt to betriggered by the olfactory stimulation either by odor or irritant of theolfactory receptors, and subsequent stimulation of the limbic system,and or other areas of the brain resulting in the complex and variedsymptoms known to be manifestations of the MCS. Some experts believethat a psychological conditioning response to odors that previouslytriggered an adverse reaction in the individual plays a role in theoverall causal mechanism for MCS. The condition MCS is assumed to bedeveloped in two steps: a) an initial phase with exposure often to ahigh concentration of a chemical substance; and b) a trigger phase,which is the subsequent set off of a number of symptoms by exposure tolow concentrations of chemicals. Researchers have shown that, in a kindof compounded Pavlovian response, when an individual is experiencingadverse effects from one chemical, other inhaled chemical odorants thatare in proximity to the individual at the time, may be added to thetriggering odorants. The number of chemicals that a MCS individual aresensitive to may increase exponentially in this manner.

While avoidance of exposure to all manner of neuro-olfactory triggers istypically the prescribed course of action, this strategy is obviouslydifficult, if not impossible, to carry out. Perfumes, personalfragrances, paints, aerosol sprays, indoor carpets, household cleaners,pollutant from building materials and mattresses are a small sample ofthe routine chemicals encountered daily which may make a neuro-olfactorysensitive person (e.g., someone who suffers from MCS) seriously ill.Such illnesses often greatly limit a subject's ability to work, shop,travel, and socialize. Many subjects become homebound due to theirillness. The illness can be severely disabling to the patient and costlyto society.

Another neuro-olfactory triggered condition is the common reaction ofnausea and or disgust upon exposure to the odorants associated withrotten flesh or food, especially protein containing foods, feces,anaerobic infections and other patho-physiologic substances such asvomitus, body discharges, and infection related exudates. While thereaction to these odors is probably determined in part by evolutionarymeans, and is beneficial in that the subject should not eat thosesubstances or avoid exposure to substances emanating those odors, it issometimes not possible to avoid them as in the case of care givers,health service personnel, and first responders. In such cases, it wouldbe desirable to provide a methodology that enables avoidance of normalphysiologic response or sensation or discomfort engendered by theexposure to such odorants. For purposes of this document such conditionsshall be referred to by the term “Neuro-Olfactory Triggered orAggravated or Related Conditions”.

Obesity is another condition or illness attributable to complex genetic,environmental and social causes where the condition is associated withan exposure to an odorant, and where the normal, usually beneficial,physiologic response may lead to an undesired outcome—obesity. Peopleare aware of increased appetite after exposure to pleasant food odors aswell as the Pavlovian increase in saliva, stomach acid and intestinalmotility—all beneficial—except when a propensity to obesity exists, andthe subject overeats. It is known in the prior art to use strongpharmacologic agents such as sodium and calcium ion channel blockers,vasoconstrictors, as well as anticholinergic drugs such as atropine andlocal anesthetics to induce temporary anosmia. All of the aforementionedactive pharmacologic agents have significant side effects, and knowntoxicity rendering them subject to careful medical supervision as wellas regulatory supervision by the United States FDA, or other supervisoryagency appropriate to the geographic location. Over dosage with thesedrugs may result in serious illness or even death.

In the previously described conditions the subject must determine theneed for avoidance of stimulation by the odorant, and this determinationis therefore appropriately labeled as completely subjective. Thisdependence upon the subjects' perceived need renders the use ofpotentially dangerous pharmacologic agents unwise and unsafe since theneeded frequency of administration depends upon many variable factors,and may result in toxicity if the potentially toxic drugs present in theagent are applied too frequently. The factors affecting the neededfrequency of administration of an agent that will induce temporaryanosmia/hyposmia include, but are not limited to: a) the concentrationof the odorant; b) the ability of the subject to avoid continuedexposure; c) the sensitivity of the chemosensors of the olfactorysensors to the odorants; d) the solubility of the odorant in the layerof mucus overlaying the nasal olfactory sensors; and e) the thicknessand viscosity of the mucous layer overlaying the sensors (since theodorant must diffuse through that layer to reach the sensor to beperceived, and to initiate and/or trigger the undesired response.)

Disclosure of the Invention

An object of the present invention is to diminish and/or prevent theperception of smells by increasing one or both of the thickness andviscosity of the mucous layer overlaying the nasal olfactory sensors,and/or to decrease the rate of diffusion of an odorant in the mucouslayer, thereby diminishing or preventing the amount of odorant reachingthe sensors. The term “prevent” is used here to describe those instanceswhere a subject cannot perceive an odor.

An additional object is to accomplish the above without any significanttoxicity so that the user may apply the remedy on an as-needed-basiswithout limiting its dosage, as would be required if potentiallydangerous drugs were employed.

An additional object of the present invention is to diminish or preventthe neurological-emotional-physical cascade of events that may occurafter exposure to olfactory stimulation by decreasing or preventing theolfactory stimulation either prophylactically or intercurrently with theexposures. The term “prevent” is used here to describe those instanceswhere the subject has either no olfactory stimulation at all, or if thesubject does have stimulation, it is at a diminished level that does notcreate a resultant effect.

The terms “olfactory nerves” and “olfactory receptors” are usedinterchangeably herein to mean the olfactory receptors in the nasalcleft, and any receptors to irritants and odorants in the nasopharynx,including those innervated by the first branch of the trigeminal nerve.Stimulation from these nerves due to exposure of their receptors toodorants or irritant chemicals can result in stimulation of the limbicsystem of the brain. This stimulation of the midbrain limbic systemaffects behavior and organs via the autonomous nervous system as well asaffecting the regulation of the hormonal balance of the body.

According to the present invention, a method for treatingneuro-olfactory triggered and/or aggravated conditions is provided. Themethod includes the steps of: a) providing a composition that includesan agent adapted to induce a level of anosmia/hyposmia in a subject,which level of anosmia/hyposmia is sufficient to substantially decreaseolfactory sensory perception within the subject and neurologic responserelated to the condition; and b) applying the composition to thesubject's olfactory receptors. The term “anosmia/hyposmia” is used todescribe the inability, or decreased ability, of a subject to smell anodor, and/or a subject's decreased sensitivity to an odor or irritant.The term mucous layer as used herein shall refer to the normal mucouslayer overlying the olfactory sensors, and the mucous layer whosecomposition is changed by the addition of the agents described in thepresent invention, such as thickening agents, oil emulsions, liposomesand the like. Odors are caused by one or more volatilized chemicalcompounds (referred to herein as “odorants”). The olfactory nerve andthe first cranial nerve include cilia or microscopic hair likeprotrusions which extend from olfactory receptor cells that are presentin the upper region of the nasopharynx into the mucous layer of theuppermost portion of the nasopharynx. These cilia (which are theterminal portions of the olfactory nerve) are covered by a layer ofmucus whose water content permits the water soluble odorant to reach thesensors by diffusion through the mucous layer. The absence of moisturein the normally present mucous layer will result in anosmia/hyposmia bynot allowing the olfaction to be captured and/or dissolved into thepredominantly aqueous mucous layer and diffused to the receptor cells.If, on the other hand, the layer of mucus normally covering the cilia isincreased in one or both of thickness and viscosity, the time requiredto diffuse through the layer of mucus to the receptor will be increased,and the odorant will be completely or partially prevented from reachingthe sensor. The mucous layer is constantly being regenerated by themucus producing cells lining the nasopharynx. The mucus containing thecaptured and/or dissolved odorant will be either expelled or swallowedprior to the odorant reaching the sensor thereby resulting in thedesired anosmia/hyposmia. Viscosity increasing agents can, in additionto increasing the viscosity, also increase the thickness of an adherentlayer to an object, especially if the layer is hygroscopic and water isavailable as is the case in the nasopharynx. Sufferers with the commoncold will frequently have increased production of viscous mucus and willoften suffer from anosmia/hyposmia, albeit with a multitude ofconcurrent undesirable effects of the viral infection. It should benoted, however, that the aforementioned upper respiratory infectionexample is not mentioned as a proposed treatment but is given as a proofthat increase layer and/or thickness of the mucous layer and orviscosity will induce temporary anosmia/hyposmia. The present inventionoperates to induce a temporary condition of anosmia/hyposmia bypermitting the subject to apply the agent by a nasal spray or drops of amixture of viscous or viscous inducing agents. The agent will beoptimally be used prior to exposure, but may be used concurrent with theexposures, and reapplied as often as necessary since the preferredembodiment of these agents are GRAS agents. “Generally Recognized AsSafe”, or “GRAS” is a United States Food and Drug Agency designation.

According to a preferred embodiment of the present invention, the agentis adapted to increase the viscosity of the mucous layer overlaying theolfactory receptors, which are located at the top of the nasopharynx.The increase in the viscosity of the mucous layer or replacement of themucous layer with a synthetic viscous mucus-like material induces alevel of anosmia/hyposmia in the subject that is sufficient tosubstantially decrease olfactory sensory perception within the subject,and consequent neurologic response. The agent increases the viscosity ofthe mucous layer to a level that is greater than the normal viscosity ofthe mucous layer.

Depending on the particular manner in which the agent is applied, it istypically desirable to incorporate a mildly acidic (pH 5.0 to 6.5)buffered isotonic aqueous fluid containing up to about 15 percent byweight, more typically about 2 to 10 percent by weight of a viscosityincreasing agent, such as a polymer or other material. Useful materialsinclude, without limitation thereto, sodium carboxymethyl cellulose,algin, carageenans, carbomers, galactomannans, hydroxypropylmethylcellulose, hydroxypropyl cellulose, polyethylene glycols,polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl chitin,sodium carboxymethyl dextran, sodium carboxymethyl starch and xanthangum and chitosans. Mucilage (a naturally occurring plant constituentwith a molecular weight of 200,000 or greater) derived from botanicalssuch as acacia gum or gum arabic, marshmallow, tragacanth, carrageen,guar, quince seed, psyllium, sterculia, comfrey, fenegreek, coltsfoot,Icelandic and Irish moss, flax or linseed, locust bean, coltsfoot, andslippery elm bark may also be employed. Combinations of any two or moreof the foregoing may be used.

According to another preferred embodiment of the present invention, theagent is used to increase the thickness of the mucous layer presentwithin the subject's nasal passages. Agents that increase the viscositywill also tend to increase the thickness of the layer, since gravitywill cause the mucous layer to fall off the sensors unless the person isupside down. The increase in mucous layer thickness induces a level ofanosmia/hyposmia in the subject that is sufficient to substantiallydecrease olfactory sensory perception within the subject, and consequentneurologic response. The agent increases the average mucous layerthickness to a level that is greater than the normal average mucouslayer thickness. The composition is applied through a nasal applicationpreferably by a nasal spray but may be applied by in the form drops, bydirect application or by sniffing of a gaseous suspension of thecomposition. As increased perception of odorants is often accomplishedby “sniffing”; i.e., shallow inspiration of air into the nose with themouth closed with the inspired volume being naturally limited to anamount approximately sufficient to fill the nasopharynx. The averagevolume of a sniff in an adult is about 200 ml. This naturally occurringsniffing mechanism is a desirable method for delivering the composition(which includes a coating agent or other active agent) to the nasalsensors while avoiding, or limiting its delivery to the lowerrespiratory tract. Alternatively, the composition may be also applied tothe nasal sensors while using a spray and holding one's breath.

According to another aspect of the present invention, oil is the agentthat inhibits diffusion of odorants and/or chemicals to olfactory nervesby preventing the odorant from dissolving in the aqueous layer. The useof oil is effective because odorants generally need to be water solubleto be capable of being sensed. The oil is disposed in particles sizedabout four microns in diameter or larger. The term “diameter” is usedherein to mean the largest cross-sectional dimension of a particle. Theoil can form a molecular layer on the outer surface of an aqueousmixture, or remain as an emulsion. Both forms will diminish access bydiffusion of the odorants through the mucous layer to the nasal sensors.The use of volatilized oil in small amounts is safe, but must becarefully formulated and administered so that inhalation of oil does notreach the lungs where it could cause damage. Application of acomposition including an oil agent by sniffing or spray while holdingone's breath is a preferred means of application.

In summary the present invention provides a method and apparatus fordiminishing or preventing the triggering of symptoms of patientssuffering from neuro-olfactory triggered illnesses or disorders (NTIs)by decreasing or preventing the neural cascade produced by deleteriousneuro-olfactory stimulation. The treatments may be used as either as aprophylactic when the patient is likely to be exposed to one of theprecipitators described above, or intercurrently when exposure isdetected. This, in turn, interrupts or decreases the sequence ofneurophysiologic and psychological events that precipitate an adversereaction in the subject. The present invention method may also be usedto induce temporary anosmia/hyposmia for the desired result ofsuppressing appetite, and helping manage obesity, as well as avoidingunpleasant reactions to offensive odors. For example, in the case ofcare givers, health service personnel, and first responders, the presentmethod can be used for treating a subject to enable the subject to avoidnormal physiologic response, sensation, and/or discomfort engendered bythe exposure to a normally objectionable odor; e.g., enable the firstresponder to work in an environment containing putrid odors, body, wasteodors, etc.

DETAILED DESCRIPTION

Chemicals capable of stimulating olfactory receptors can access thereceptors in several different ways. A chemical that is volatile enoughto reach the nasopharynx can be inhaled with breathed air. An odorantchemical or combination of chemicals that is/are sufficiently watersoluble can dissolve into, and pass through, the aqueous surface of thenasal mucus, provided water is present on the surface of the receptor.Chemical odorants must diffuse through the aqueous layer in the mucusoverlying the sensor cells to reach the receptors. The efficiency of thediffusion, however, is dependent on factors including the thickness andviscosity of the layer that the chemical must transverse. Odorantchemicals may be sufficiently lipid-soluble to permit them to passthrough the cell membrane of the sensor cells, and thereby stimulate theolfactory receptors. Of course, once such a chemical reaches the sensorcell, stimulation and the neurological response that normally resultsdepends upon the ability of the sensor cell to send its neural signal tothe brain. If the stimulating chemical does not reach the olfactoryreceptor, or if the receptor is unable to send its signal, theneurological response associated with the stimulation will be avoided orreduced to the extent the stimulation is reduced. Embodiments of thepresent invention method are operable to decrease or prevent thestimulation of the olfactory receptors, and thereby prevent or decreasethe neurological response to olfactory stimulation and the resultantneuro-olfactory triggered or related or exacerbated conditions.

Mucin is normally present in the nasal pharynx as an important componentof the mucus. Mucins are a family of high molecular weight, heavilyglycosylated proteins (glycoconjugates) produced by epithelial tissuesin humans and other animals. One of the key characteristics of mucin isits ability to form gels. In most gel-like secretions, mucin provideslubrication and participates in cell signaling, chemical barrierformation, etc. Mucus is a liquid secretion on the mucosal surface,which contains mucins as well as other important constituents includingantibodies and electrolytes. The main component of the mucus is water.The lubricity and viscosity of mucus is a function of its mucinglycoproteins. An additional property of mucins and compounds similar tomucins, whether natural or synthetic is their increased adherence tomucosal surfaces. The presence of mucins within mucus helps to increasethe depth of the mucous layer and increase the viscosity of the layer.

The present invention emulates this process for the purpose of treatingneuro-olfactory triggered illnesses or disorders (NTIs). In someembodiments, a synthetic or animal or plant derived agent is providedwithin a composition that is applied to the subject to facilitate theproduction of a mucous layer (referred to herein as a “derived” mucouslayer) within the subject's nasopharynx region. The term “synthetic oranimal or plant derived agent” as used herein refers to an agent thatis: a) synthetically derived from, for example, chemical, animal, orplant matter; and b) adapted to increase one or both of the viscosityand thickness of the mucous layer within the subject; e.g., cause theviscosity of the layer to increase to a viscosity greater than water.The increased viscosity of the mucus decreases the ability of theodorant or irritant chemical to diffuse through the mucous layer andsubsequently physically or chemically access the olfactory receptorssince the diffusion rate is typically inversely related to the viscosityand thickness of the mucous layer. An agent synthetically derived fromchemical or plant matter is advantageous because it eliminates thepossibility of the animal derived agent caring infectious diseaseparticles (such as prions) that may be resistant to ordinarysterilization. Alternatively, “disease free” agents could bebioengineered from recombinant DNA. A synthetically derived mucous layerhas the clinical advantage of having a lower incidence of allergenicityand is a preferred embodiment of the present invention. In somepreferred embodiments, a viscosity increasing agent is included withinthe composition, which agent is adapted to increase the viscosity ofnasal mucus within a subject to about 150 Poise or greater.

The pharmaceutical compositions described herein are prepared in amanner known to those skilled in the art, for example, by means ofconventional dissolving, lyophilizing, mixing, granulating, orconfectioning processes. Methods well-known in the art for makingformulations are found, for example, in Remington: The Science andPractice of Pharmacy (21st ed.), ed. A. R. Gennaro, Lippincott Williams& Wilkins, 2005, and Encyclopedia of Pharmaceutical Technology, ed. J.Swarbrick, Informa Healthcare, 2006, each of which is herebyincorporated by reference.

The pharmaceutical compositions described herein may contain a bufferingagent. Any pharmaceutically acceptable buffering agent may be used inthe composition, including, e.g., phosphate, borate, citrate, acetate,or carbonate. Preferably, the buffering agent will produce a pH that isslightly acidic, less than 7, and preferably between 5 and 6.9 sinceacidic conditions cause a more viscous mucus. Suitable acids (e.g.,hydrochloric acid) and bases (e.g., sodium hydroxide) may be used toadjust the pH of the pharmaceutical composition. Tonicity agents may beadded to adjust the tonicity of the pharmaceutical composition withrespect to the tonicity at the site of administration. Hypertonicity canalso be employed since the mucins will swell by adsorption of waterpresent in the naturally secreted and present mucus. Exemplary tonicityagents include, e.g., sodium chloride, potassium chloride, dextrose,mannitol, and sorbitol. Humectants, or water-binding compounds, may beadded to the compositions described herein to aid in the retention ofmoisture. Exemplary humectants include, e.g., glycerin, propyleneglycol, and polyethylene glycol. Humectants may also be added to, e.g.,surfaces to which the pharmaceutical composition is applied to keep thesurface hydrated and moist. The pharmaceutical composition may includepreservatives in an amount sufficient to prevent microbial growth in thecomposition when stored. Preservatives may include, e.g., benzylkoniumchloride, chlorohexidine gluconate, polyhexamethylene biguanide, andascorbic acid.

The pharmaceutical compositions according to the invention may beformulated to release the active compound immediately uponadministration (e.g., targeted delivery), or at any predetermined timeperiod after administration, using controlled or extended releaseformulations to decrease the duration of action.

In some embodiments, the present method utilizes an agent that isoperable to physically coat the surface of the mucous layer coating theolfactory receptors. An example of such an agent is a vegetable,mineral, or synthetic oil that would act as physical barrier for theodorant or irritant chemical by naturally forming a surface coating onthe mucous layer and preventing the water soluble odorants from enteringthe aqueous content of the mucous layer. The oil coating of theolfactory receptors in the nose will also decrease the amount ofodorants reaching the olfactory receptors by preventing odorants thatare oil soluble from leaving the coating layer. The oil layer couldtherefore work as both a barrier to water soluble odorants as well asaffinity capture of the oil soluble odorants. The oil may therefore bedescribed as substantially inhibiting entry of an odorant into themucous layer overlying nasal olfactory sensors within the subject. Anoil that creates an oil/odorant suspension can be combined with asynthetically derived agent, if desired, that produces an increase inthe viscosity and/or thickness of the subject's mucous layer therebydelaying the diffusion through the mucous layer overlying the nasalolfactory sensors The concentration of the oil may range from about oneto one hundred milligrams of oil within ten milliliters (1-100 mg/10 ml)of isotonic aqueous spray, and optimally contains unscented oil such asmineral oil.

Liposomes are another agent that can be used to decrease the ability ofan odorant or irritant chemical from reaching a subject's olfactoryreceptors. The liposomes can perform this function in two different, butrelated, manners. On the one hand, liposomes can be used to increase theviscosity of a mucous layer, and thereby decrease the chance of anodorant diffusing through the mucous layer and reaching the olfactoryreceptors prior to the mucus being expelled or ingested. On the otherhand, liposomes can also be used to absorb odorants. The absorbedodorant(s) are less likely to reach the olfactory receptors because theyare disposed within the liposome structure and because the liposomestypically have limited mobility within the viscous mucus. The liposomesmay therefore be described as substantially inhibiting entry of anodorant into a mucous layer and/or delaying the diffusion through themucous layer overlying the nasal olfactory sensors within a subject.

In preferred embodiments of the present invention, increased viscosityof the mucus is used to block odorants from reaching the olfactoryepithelium. Mucous films function as both mechanical buffers andmicro-filters, and in the case of this invention, as an affinity filterby capturing and containing the odorant. The mucus containing theentrapped odorants is either expelled as it is replaced by naturalmucus, or swallowed, as it is nontoxic. A patient may be directed toperiodically use an intranasal spray containing an agent adapted toinduce a level of anosmia/hyposmia in a subject to safeguard againstexposure to chemical odorants.

A mucin containing aqueous solution suitable for nasal use may bederived from animals (e.g., see U.S. Pat. No. 4,438,100) or may bemanufactured from polyethylene oxide (e.g., see U.S. Pat. No.3,767,789), or manufactured from mixtures of microcrystalline celluloseand alkali metal carboxyalkylcellulose (e.g., see U.S. Pat. No.6,565,832) all three of which are incorporated by reference herein intheir entirety. Additionally, water soluble cellulose derivatives suchas methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,carboxymethyl cellulose, etc. may serve as synthetic mucus and act asmechanical buffers and affinity filters when applied to the nose. Thenature and composition of these synthetic mucus-like materials is wellknown in the art and are employed as components of nasal sprays toincrease the viscosity of the applied medication so as to prevent theirdripping in to the nasopharynx. Examples of such medications containingviscosity-increasing agents in the form of synthetic mucus-like materialinclude: Afrin No Drip™, Vancenase AQ™, and Vick's Early Defense™ nasalsprays. In all the aforementioned products, however, the viscosity agentis always administered with an active pharmacologic agent, generally adecongestant or steroid, in a manner that designed to stop the drippingof the medication from the applied medication, and increase thesubject's ability to breathe. As such, these products are notadministered to decrease olfactory sensation, but rather teach away fromsuch an application, and are in all cases combined with medications. Inthe present method, an agent adapted to induce a level ofanosmia/hyposmia in a subject is administered to a subject in an amountand frequency that produces a level of anosmia/hyposmia that issufficient to temporarily substantially decrease or abolish olfactorysensory perception within the subject, and therefore the subsequentneurological response related to the condition. The aforesaid products,and others like them, cannot be used in the manner described within thepresent invention without the toxicity or side effects created byoverdosing the medication contained within the product.

A preferred embodiment of the present invention is one in which the onlyactive materials within the composition are GRAS materials, and one inwhich the user may use it as often as needed to accomplish the goal ofdecreasing or abolishing olfactory sensation during extended periods ofexpected, or actual, exposure to the problematic odorant or irritantchemical. Within the present invention, the viscosity of the appliedcomposition (including the agent) is preferably greater than theviscosity of water, but sufficiently low enough to allow spraying of thematerial for deposition in the sensory area of the nasopharynx. Anon-Newtonian liquid may be optimally used so that the stationaryviscosity is higher than the viscosity under shear forces induced byspraying, thereby permitting easy deposition by spraying, and adequateretention on the mucosal surface. The composition may be provided in adosage form that is suitable for intranasal administration either in theform of a spray or drops of a suspension, emulsion, solutions, gels, andhydro gels, which gels may be referred to as being in a topical form.The composition may be sterile.

Agents that are useful to create a desirable applied material viscosityinclude mixtures of microcrystalline cellulose and an alkali metalcarboxyalkylcellulose. An example of such a mixture in a commerciallyavailable form is sold by FMC Corporation, Philadelphia, Pa. U.S.A. asAvicel™ RC-591. This material contains approximately 89 weight percentmicrocrystalline cellulose and approximately 11 weight percent sodiumcarboxymethylcellulose, and is known for use as a suspending agent inpreparing various pharmaceutical suspensions and emulsions. Certaincompositions of the present invention may contain at least about 2.5weight percent of the cellulose/carboxyalkylcellulose compound mixture,generally not exceeding about 10 weight percent to avoid producing highviscosities which impede spraying with the usual devices. Anothermixture that can also be used (also available from FMC Corporation) isAvicel™ RC-581, which has the same bulk chemical composition as theRC-591. Alternatively, microcrystalline cellulose and alkali metalcarboxyalkylcellulose are commercially available separately, and can bemixed in desired proportions for use in the invention, with the amountof microcrystalline cellulose preferably being between about 85 andabout 95 weight percent of the mixture for both separately mixed andco-processed mixtures.

Depending on the intended application, it may be desirable toincorporate up to about 10 percent by weight, more typically about 0.5to about 5 weight percent, of an additional rheology-modifying agent,such as a polymer or other material. Useful materials include, withoutlimitation thereto, sodium carboxymethyl cellulose, algin, carageenans,carbomers, galactomannans, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyethylene glycols, polyvinyl alcohol,polyvinylpyrrolidone, sodium carboxymethyl, chitin, sodium carboxymethyldextran, sodium carboxymethyl starch and xanthan gum. Combinations ofany two or more of the foregoing are also useful.

The more simple techniques commonly used to determine rheologicalproperties of fluid compositions, including the Brookfield rotatingkinematic viscometer which measures torque transmitted through a sampleusing a rotating spindle, do not yield the most meaningful informationfor non-Newtonian fluids such as those of this invention. Since theviscosity of the thixotropic composition varies inversely according tothe magnitude of shear force being applied, and the viscosity increasesover time following withdrawal of the shear force, it is more useful tomeasure and compare complex viscosity. A mathematical derivation ofcomplex viscosity can be found in H. A. Barnes et al., An Introductionto Rheology, Elsevier, N.Y., 1989, particularly at pages 46-48. Complexviscosity from a oscillatory applied shear is defined by these authorsat page 48 as being: “the ratio of the shear stress . . . to the rate ofshear . . . ” Units for expressing complex viscosity (typicallyrepresented by the symbol η*) are in Pascal seconds (Pa·s.), equivalentto newton seconds/meter² in the International System of Units.

The above-described treatments or combinations of the treatments willenable people with odorant or irritant chemical sensitivities to leadmore productive, fulfilling lives, less circumscribed by this illness.One significant advantage provided by the present invention is thetemporary, reversibility of the induced anosmia/hyposmia. A subject canchoose when to treat herself with the medication described in thepresent invention. The patient may elect when to practice the method,and to some degree the dosage as well. As a result, the subject cantailor the practice to their specific needs and thereby have moreability to avoid debilitating symptoms. For example, the compositionprovided in nasal spray form may be administered once, twice, threetimes, four times, or five times each day, or in other quantities andfrequencies as subjectively needed by the patient to prevent detrimentalolfactory stimuli. The duration of therapy can be intermittent orregular depending upon the exposure to the stimuli. In cases asdescribed in the present invention where there are no activepharmacologic agents such as local anesthetics or anticholinergics (ananticholinergic agent is a substance such as atropine that blocks theneurotransmitter acetylcholine in the central and the peripheral nervoussystem) there would be no significant limitation as to frequency of use,other than instructions to diminish use or avoid use if local irritationor side effects occur.

The invention will be further described by means of the followingexamples, which are not intended to limit the scope of the invention inany manner.

In a first example, a composition in the form of a nasal spray or dropsthat includes an agent adapted to induce a level of anosmia/hyposmia ina subject is administered to a subject. The agent is adapted to increaseone or both of the viscosity and thickness of the mucus layer within thesensory area of the subjects' nasopharynx. The thickness of the normalnasal mucus ranges from 5 to 100 microns as reported in the literature.Agents described in the background material of this application thatincrease the viscosity will generally also increase the depth of themucous layer. The increased viscosity and/or thickness of the mucouslayer decreases the ability of the odorant or irritant chemical to passthrough the mucous layer, and subsequently physically or chemicallyaccess the olfactory receptors. In most cases, the odorant or irritantchemical becomes trapped within the mucous layer, and is subsequentlyeither expelled as nasal secretions or swallowed, and in either case,the olfactory sensation is prevented or significantly diminished. Thelevel of anosmia/hyposmia created by the agent acting on the mucouslayer is sufficient to substantially decrease the olfactory sensoryperception within the subject and the neurologic response related to thecondition. Since mucus production is continuous from the mucousproducing cells on the mucous membrane lining the nasopharynx, therepeated application of thickening agents and/or viscosity increasingagents will serve to prevent, and/or decrease odorants present in thesurface layer of the mucus from ever reaching the olfactory sensor. Theentrapped and/or dissolved odorants will be expelled from the nose andor swallowed prior to reaching the olfactory sensors thereby causinganosmia/hyposmia.

In a second example, the agent included in the composition includes anoil/water emulsion where the particles of oil are of sufficient size soas not to pose the risk of aspiration induced lipoid bronchitis orpneumonitis. Oil particles above about four microns (4μ) in size, with aparticle size of about five to thirty microns (5-30μ) in diameter arepreferred to avoid inadvertent passage into the alveoli of the lungs.The composition may be administered by the subject as previouslydescribed. This method of administration will help prevent aspiration ofthe particles into the bronchial tree and lungs. The gaseous volume ofspray may be limited to less than 200 cc/per spray, and proportionallyless for children, and the spray administered while holding ones breath.The oil is used to temporarily occlude the nasal receptors from reactingwith the odorant. Odorants are typically water soluble and of smallmolecular size. Oil provides a temporary barrier between the odorant andthe olfactory receptors. Most, if not all, of the odorant will not makecontact the olfactory receptors, thereby preventing or mitigatingolfactory-triggered episodes.

In a third example, the agent included in the composition includes oneor more liposomes. Liposomes are used for drug delivery due to theirunique properties. A liposome encapsulates a region of aqueous solutioninside a hydrophobic membrane. Dissolved hydrophilic solutes cannotreadily pass through the lipids. Hydrophobic chemicals can be dissolvedinto the membrane, and in this way liposome can carry both hydrophobicmolecules and hydrophilic molecules. Initially, the liposomes canoperate to coat the mucous layer as well as the olfactory receptors. Asthe oil/lipid external layer of the liposome dissolves, the liposome canthen release its internal water-soluble contents. In some embodiments,the water soluble contents can include a mildly acidic buffered solutionin the ph range of less than 7 to increase the viscosity of the mucouslayer since the constituents of the mucous layer are known to becomemore viscous with increasing acidity. The liposomes can be used withinthe present method as solitary agents within the composition, or incombination with other agents; e.g., agents that increase the viscosityor thickness of the mucous layer.

Embodiments of the present disclosure include compositions in athixotropic form that also possesses Bingham plastic behavior (referredto hereinafter as a “thixotropic composition”). For example, acomposition according to the present disclosure may be a gel suspensionthat is sufficiently viscous while in a resting state so as to assume asemi-solid form (sometimes referred to as a “viscous gel”). If an amountof shear stress is produced within the semi-solid form of thecomposition (e.g., by application of a force such as an agitating force,or a force associated with pumping the composition, or a forceassociated with a pressurized displacement of the composition from avessel, etc.) that exceeds the yield point of the gel suspension,however, the portion of the composition subjected to the shear stresschanges its form into a lower viscosity form that acts substantiallylike a liquid and is therefore in a flowable (e.g., sprayable) form;i.e., the composition exhibits “shear thinning properties”. In theliquid form, the thixotropic composition can be readily transported(e.g., sprayed from a spray bottle). Within a very short period of time(e.g., typically less than five (5) seconds) after the shear stresscausing force is removed from the thixotropic composition, however, thecomposition returns to a semi-solid form. In some embodiments, thecomposition returns to a semi-solid form in less than about one second.The threshold dependent shear thinning aspect of the thixotropiccomposition causes the thixotropic composition to remain in itssemi-solid form during storage or ordinary movement of the containerholding the composition. Because thixotropic compositions according tothe present disclosure attain equilibrium viscosity relatively quickly(although likely not instantaneously) in the absence of shear stress(i.e., the amount of shear stress adequate to transform the compositioninto a liquid), the compositions may also be described as pseudoplasticfluids.

A “thixotropic composition”, as that term is used herein, may be definedas a composition that is a gel suspension that: a) under roomtemperature (about 68° F. to about 77° F.; i.e., about 20° C. to about25° C.) and in a resting state, is in a semi-solid form; b) can betransformed from the aforesaid semi-solid form into a liquid form uponthe introduction of sufficient shear stress into the composition (e.g.,by application of an agitating force); and c) returns to the aforesaidsemi-solid form in a relatively short period of time upon dissipation ofthe shear stress and re-assumption of a resting state. The fact thatthixotropic compositions according to the present disclosure are in asemi-solid form when the composition is at rest, and that it takes theintroduction of a predetermined minimum amount of shear stress into thecomposition to cause a change in state from the semi-solid form to theliquid form, the thixotropic composition may be described as havingcharacteristics like those of a Bingham plastic fluid. Like a Binghamplastic fluid, shear stress can be can be applied to the thixotropiccomposition, but the composition will not change state and flow until acertain amount of shear stress (typically referred to as the “yieldstress”) is present within the composition. In most embodiments, thethixotropic composition is configured such that the amount of shearstress required to change the form of the thixotropic composition from asemi-solid form to a liquid form (i.e., the “threshold” amount) cannotbe reached unless the composition is purposefully agitated, pumped, orthe like. For most of the applications described herein, the thresholdamount of shear stress may be defined as the amount of shear stressproduced with the thixotropic composition is subjected to onegravitational force (i.e., “1 G”). In other words, walking with orcarrying a container of thixotropic composition under normal conditionswill not cause the thixotropic composition to change from a semi-solidform to a liquid form. To illustrate further, in most of theapplications described herein a thixotropic composition subjected togravity (i.e., a “1 G” force) will not transform from a semi-solid formto a liquid form. Hence, in such embodiments an amount of thixotropiccomposition disposed in a less-than-full container (residing in asemi-solid form in the bottom of the container) that is inverted (turnedupside down) will not change form and flow due to gravity alone. Beyondthe yield stress point, the flow rate of the composition will increaseas a function of the increasing shear stress. In contrast, a Newtonianfluid has a “zero” yield stress in that it will flow upon theintroduction of any amount of force. In the liquid form, and in theformulations described herein, the thixotropic composition can besprayed through a spray applicator such as a standard nasal sprayapplicator and/or may be readily manually pumped and expressed in sprayform. For example, for certain embodiments of the present thixotropiccomposition a squeeze type spray application can be used by applyingsufficient force to the flexible container. The force applied to thecontainer will create sufficiently high shear stress in the thixotropiccomposition to cause at least a portion of the composition to change toa liquid form which can then be expelled through the nozzle of theapplicator in a spray form. In other embodiments of the presentthixotropic composition, a positive-displacement type piston pump ispreferable. The action of the pump produces the level of shear stresswithin the thixotropic composition required to liquefy the composition,and the liquefied composition can then be sprayed. An advantage of usinga positive-displacement type pump is that the volume per spray ofthixotropic composition transformed from semi-solid to liquid form isless than other type spray mechanisms such as a squeeze bottle.Maintaining a significant portion, virtually the entire unsprayedportion, of the thixotropic composition in semi-solid form hasadvantages with regard to inhibiting microbial growth, and a decrease inthe need for a preservative or a anti-microbial as will be explainedbelow.

As indicated above, present disclosure thixotropic compositions mayinclude one or more viscosity agents with an aqueous carrier. Examplesof acceptable viscosity agents include, but are not limited to,microcrystalline cellulose, carboxyalkycellulose,sodium-carboxymethylcellulose, and the like. Additional examples ofacceptable viscosity agents as described above. In some embodiments, athixotropic composition may also include rheology-modifying agents asdescribed above. Preliminary testing indicates that a blend ofmicrocrystalline cellulose (“MC”) and sodium-carboxymethylcellulose(Na-CMC) performs particularly well as a viscosity agent within athixotropic composition. A specific non-limiting example of a viscosityagent that can be used within a thixotropic composition according to thepresent disclosure is VIVAPUR® MCG produced by JRS Pharma LP ofPatterson, N.Y. USA, and in particular VIVAPUR® MCG 811P. The presentdisclosure is not limited to any particular aqueous carrier. In someembodiments, the aqueous carrier may be normal saline, buffered saline,distilled water, de-ionized water, or saline made from de-ionized wateror the like. 7

As indicated above, a composition according to the present disclosuremay include a viscosity agent in the range of about 2.5% to about 10% byweight. We have now discovered, however, that useful thixotropiccompositions according to the present disclosure may in fact include aviscosity agent in the range of about 2.5% to about 15% by weight. Aswill be indicated below, preliminary testing indicates that presentthixotropic compositions function better in particular sub-ranges ofviscosity agent depending on the application at hand.

In some applications of the present disclosure compositions, thecomposition is configured to possess muco-adhesiveness. The term“muco-adhesiveness” refers to the property of a substance to adhere tomoist mucous membranes. The American Society of Testing and Materialshas defined it as the state in which interfacial forces, which mayconsist of valence forces, interlocking action or both, hold twosurfaces together. The muco-adhesiveness of certain present compositionshelp to prolong the residence time of an applied layer of the presentcomposition on a mucous membrane.

In some embodiments, a thixotropic composition according to the presentdisclosure may be sterilized by heat or gamma radiation.

The presently described methods and compositions, particularly thosecompositions in thixotropic form, provide significant mechanisms fortreating neuro-olfactory triggered and/or aggravated conditions inaddition to those described above and in subsets of those conditionsdescribed above.

Studies have indicated a causal link between increased olfactorysensitivity and nausea and vomiting. See Hyperolfaction and hyperemesisgravidarum: what is the relationship? Erick, M., Nutr. Rev. 53, 289-295(1995); Linking olfaction with nausea and vomiting of pregnancy,recurrent abortion, hyperemesis gravidarum, and migraine headache,Heinrichs, L., Am. J. Obstet. Gynecol. 186, S215-S219 (2002); and Nauseaand Vomiting in Pregnancy, Niebyl, J. R., N. Engl. J. Med. 363,1544-1550 (2010). As described in Pregnancy and Olfaction: A Review, E.Leslie Cameron, Frontiers in Psychology, Volume 5, Article 67 (February2014), about seventy five percent of all women experience nausea andvomiting during pregnancy, and a study by Cantoni et al. reported that58% of 500 women responded that there were odors that caused nauseaduring pregnancy. See Changes in olfactory perception and dietary habitsin the course of pregnancy: a questionnaire study, Cantoni et al., Chem.Senses 24, 58 (1999). A study by Swallow et al. reported that in asample of 273 pregnant women, those who were adversely affected by odorsscored higher on a measure of the severity of their nausea and vomiting.See Women with nausea and vomiting in pregnancy demonstrate worse healthand are adversely affected by odours, Swallow et al., J. Obstet.Gynecol. 25, 544-549 (2005). Hence, the link between increased olfactorysensitivity and nausea and vomiting is described as strong, particularin select groups such as pregnant women. A composition as describedherein, particularly one in thixotropic form, can be used to induce alevel of anosmia/hyposmia in a pregnant woman that decreases the woman'solfactory sensory perception and thereby decreases or eliminates thewoman's olfactory related nausea and/or vomiting. Preliminary testing todate indicates that when a thixotropic composition according to thepresent disclosure is applied into a nasal cavity to form a coatinglayer sufficient to induce a level of anosmia/hyposmia in a pregnantwoman that is sufficient to decrease olfactory sensory perception andthereby decrease or eliminate olfactory related nausea and/or vomiting,the thixotropic composition preferably includes a viscosity agent in therange of about 4.0% to about 8.0% by weight. The present thixotropiccomposition may be applied via spraying to form a coating layer withinat least a portion of the nasal cavity prior to exposure to an odorlikely or known to cause nausea and/or vomiting, and may be repeated asneeded. In some instances, the aforesaid composition may be applied viaspraying to form a coating layer within at least a portion of the nasalcavity after an initial exposure to the offending odor to mitigate thenauseous effect.

To illustrate the utility of the present thixotropic compositions,several tests were performed. Because the measurement of viscosity in athixotropic composition is problematic, the tests were structured tosimulate applications as described herein. In addition, the tests werestructured to simulate forces that may be encountered by a thixotropiccomposition as described herein (e.g., thixotropic compositions involumes of one to several ounces disposed within a container) toevaluate the performance characteristics of the various thixotropiccompositions. The tests involved preparing different thixotropiccomposition formulations, each containing a different by weightpercentage of viscosity increasing agent within the composition. In someof the tests, each of the different thixotropic compositions weredeposited in a particular tube configuration and allowed to assume an atrest state. Once all of the thixotropic compositions were in an “atrest” state (i.e., had assumed a semi-solid form), the tubes wereinverted 180 degrees to evaluate the ability of the thixotropiccompositions to remain in their semi-solid form when subjected togravity. The test indicated that thixotropic compositions having aviscosity agent as described herein at a percentage of at least 4% byweight showed favorable characteristics. In other tests, each of thedifferent thixotropic compositions were deposited into a pump spraycontainer and allowed to assume a semi-solid form. Subsequently, thedifferent thixotropic compositions were each sprayed on respective glassslides from a defined distance and the sprayed composition was allowedto rest on the slide for a period of five seconds. The slides wereoriented horizontally (i.e., perpendicular to a gravitational vector)during the spraying process. At the end of the allotted time, each slidewas rotated ninety degrees so as to be in alignment with thegravitational vector, and the sprayed material was observed for flow.This process was repeated a number of times wherein subsequent sprayswere applied to the already applied material. The tests indicated thatthixotropic compositions having a viscosity agent as described herein ata percentage of at least 4% by weight showed favorable characteristics;e.g., the sprayed thixotropic composition had reverted to its semi-solidform and did not, therefore, exhibit any appreciable flow. In the testinvolving a thixotropic composition having a viscosity agent by weightof 8%, for example, thirteen sprays of the thixotropic composition wereapplied to the slide prior to the thixotropic composition exhibitingflow relative to the slide. Before the composition began to flow, thelayer of thixotropic composition amassed on the slide from theconsecutive sprays had a thickness of about six millimeters.

We have also discovered that thixotropic compositions according to thepresent disclosure may be utilized for subject's suffering fromepistaxis (bleeding from the nose). Epistaxis is a very common medicalproblem that can range from a few drops of blood a minute to lifethreatening bleeding rate. Over 90% of nose bleeds occur in theantero-inferior region of the nasal septum (sometimes referred to as“Kiesselbach's plexus”). Approximately 5% to 10% of nosebleeds arisefrom the posterior nasal cavity (sometimes referred to as “Woodruff'splexus”), which region is not easily accessible. Most nosebleeds areself-limiting and respond to rest and prolonged application of simplepressure on the soft tissue of the nose below the nasal bones. Thosenosebleeds that do not stop can require costly emergency medical care.Existing techniques available to stop persistent nosebleeds includecauterizing the bleeding vessel, or packing the nose with gauze or aballoon like device to apply local pressure. In some instances a topicalmedication may be applied to induce clotting. The aforementionedtreatments may be invasive, expensive and/or uncomfortable, and may beonly marginally effective (or possibly ineffective) due to theirinability to access the ruptured blood vessels or tissue that are thesource of the bleeding.

A thixotropic composition according to the present disclosure may besprayed into a nasal cavity to form a coating layer within at least aportion of the nasal cavity. Because the thixotropic composition can besprayed in liquid form, it is possible to apply the thixotropiccomposition to regions of the nasal cavity that may be difficult orimpossible to reach using prior art techniques (e.g., regions of theposterior nasal cavity, also known as “Woodruff's plexus”). The subjectsuffering the nose bleed may hold his or her breath during the sprayapplication, or may sniff during application to facilitate deposition ofthe thixotropic composition throughout the distribution of the spraywithin the nasal cavity. Within a relatively short period of time, theliquid thixotropic composition will transform back into a semi-solidform; i.e., a coating layer. Depending upon the extent of the bleeding,it may be necessary to use multiple applications of the thixotropiccomposition with each application separated by a short period of time(5-10 seconds). Multiple applications will enable the user to increasethe thickness of the thixotropic composition coating layer. In thisparticular application, the present disclosure may include a specializedapplicator that is configured to direct the liquefied thixotropiccomposition in predetermined directions; e.g., an applicator nozzlehaving two exit apertures, with one exit aperture oriented to direct aportion of the sprayed composition towards the lower anterior nasalseptum and the exit aperture oriented to direct a portion of thecomposition into the nasal cavity. Once the thixotropic composition isreestablished as a semi-solid, it forms a semi-solid plug (also referredto as a coating layer) on top of the bleeding site and inducescoagulation by direct effect of the microcrystalline cellulose, which isshown to activate platelets and promote coagulation. In addition, thethixotropic composition includes an aqueous carrier (e.g., distilledwater, saline, etc.) that maintains a moist environment within the nasalcavity and thereby mitigates dryness that is often a cause orcontributing factor in causing epistaxis. The thixotropic composition,which may be in pharmaceutically inactive form, remains in place for aperiod of time until it slowly disintegrates, or is expelled by thesubject. Preliminary testing to date indicates that when a thixotropiccomposition according to the present disclosure is used to as atreatment for epistaxis, the thixotropic composition preferably includesa viscosity agent in the range of about 6.0% to about 15.0% by weight,and a thixotropic composition having a viscosity agent of about 8% byweight particularly useful.

The application of the thixotropic composition by spray is particularlyuseful in reaching areas of minor to slight bleeding where cauterizationand or surgical ligation of a vessel are not needed or desirable. Otherpotential conditions where the thixotropic composition may be appliedinclude surgical hemostasis, skin and soft tissue injuries, injectablevascular plugs, soft tissue filler and/or expander, lung air leakage.

In regards to surgical hemostasis, there is a major need for hemostasisadjuncts above and beyond ligatures and sutures in surgical procedures.All available products for this purpose have benefits and liabilities.(e.g., See “How I do it: Utilization of high-pressure sealants in aorticreconstruction”, Elefteriades, J., J Cardiothorac Surg 2009; 4:27;“Improving Outcomes through the Use of Surgical sealants for AnastomoticSealing during Cardiovascular Surgery”, DeAnda et al., J Card Surg 2009;24:325-33) The adhesive properties of the present thixotropiccomposition make it attractive as a topical, spray-on sealant forvascular anastomoses and raw surfaces (e.g., liver, pancreas, etc.) insurgery.

In regards to skin and soft tissue injuries, the adhesive properties ofthe thixotropic composition make it suitable for in-the-field andemergency department control of bleeding from wounds, cuts, andabrasions.

In regards to injectable vascular plugs, in many circumstances internalbleeding is treated, in the current era, by selective angiographicinjection of materials intended to plug bleeding vessels. Amongsubstances injected for this purpose are wires, coils, clots, thrombin,and Gelfoam. The present thixotropic composition has suitable propertiesfor injection for this purpose of plugging a bleeding vessel. Also,because the present thixotropic composition will be cleared slowly bythe subject's body, long after its hemostatic purpose has beencompleted, no residual metal or other foreign material will remain inthe vascular tree.

In regards to sealing air leaks of a lung, the lung parenchymal tissuemay leak spontaneously (e.g. spontaneous pneumothorax, with or withoutCOPD) or during lung surgery (raw lung surface). The adhesivecharacteristics of the present thixotropic composition make it suitablefor sealing such parenchymal air leaks from the lung, either by directsurgical application, or by injection through the chest wall.

For all of the aforementioned causes of bleeding that require a strongersemi-solid thixotropic composition, the cellulose polymers employed inthose specific cases may be cross linked utilizing means known to thoseskilled in the field so that their structural strength is increased butat the expense of their delayed clearance from the body.

The powerful association of olfaction with taste and appetite is wellknown and experienced by all. The aroma of an appealing food willincrease salivation and sensations of hunger. Conversely, the smell ofan unpleasant odor may significantly decrease appetite. The unpleasantodors may be environmental, pathophysiologic as a result of an illnessor local infection, present in a medicinal product, or naturally presentin a food all of which may be a cause of decreased appetite and resultin harmful decreases food intake. Odors may also induce conditionedreflex induced loss of appetite. The induction of temporary anosmia orhyposmia may be utilized in both conditions to prevent overeating, as anadjunct to dieting and to allow sufficient eating when a subject isunavoidably exposed to appetite decreasing odors. A composition asdescribed herein, particularly one in thixotropic form, canalternatively be used to induce temporary anosmia/hyposmia to assist ina temporary reduction of appetite, or to avoid the olfactory triggeredonset of a food craving or the odor induced loss of appetite. Theaforesaid composition may be applied via spraying to form a coatinglayer within at least a portion of the nasal cavity prior to exposure tothe appetite increasing aroma or the appetite-decreasing odor, and maybe repeated as needed. In some instances, the aforesaid composition maybe applied via spraying to form a coating layer within at least aportion of the nasal cavity after an initial exposure to the appetiteincreasing aroma or the appetite-decreasing odor, and may be repeated asneeded.

A significant aspect of the presently disclosed thixotropic compositionsrelates to their potential for the avoidance of, or decreased need for,preservatives and/or anti-microbial agents in certain thixotropiccomposition products. This is particularly significant for users such aswomen who are pregnant (or are trying to get pregnant) who wish to avoidthe use of products containing preservatives and/or anti-microbialagents, or users that have real or perceived fears of teratogenicity dueto the presence of preservatives and/or anti-microbial agents, or forusers who are susceptible to medication induced inflammation of thenasopharynx (i.e., rhinitis medicamentosa) that may be triggered bypreservatives and/or anti-microbials present within a composition, orusers who are afflicted by multiple chemical sensitivity (MCS).

Nasal spray compositions (or compositions used elsewhere on the humanbody) very often contain preservatives and/or anti-microbial agents.Preservatives may be included to improve the shelf life of thecomposition. Anti-microbial agents may be included to kill potentiallyharmful bacteria, particularly in those compositions dispensed in anapplicator that is intended for multiple uses and may be used over anextended period of time (e.g., a composition administered in a nasalspray applicator). Preservatives and anti-microbial agents are apotential source of irritation and other adverse reaction. Thixotropiccompositions according to the present disclosure may decrease oreliminate the need for preservatives and/or antimicrobials inapplications such as but not limited to topical, oral, or vaginalpharmaceutical or personal care products delivered by spray or containedin a sealed compressible or expressible container. It is ourunderstanding that in those thixotropic compositions that may requiresome amount of preservative, it is often possible with the presentthixotropic compositions to decrease the amount of required preservativeby 50% or more. In some applications, it may be possible to avoid theneed for absolute sterility in a composition. In surgical applicationsabsolute sterilization is necessary, but preservatives may be omittedbecause surgical applications would likely be a single use application.

The semi-solid form of the present thixotropic composition at restsignificantly reduces and may prevent microbial growth because thesemi-solid form inhibits and may prevent diffusion of nutrients and/ormobility of the microorganisms within the semi-solid thixotropiccomposition. Under certain conditions, microbial growth may occur on thesurface of a semi-solid thixotropic composition, but the surfaceresiding organisms are limited to local nutrients. Once local nutrientsare exhausted, the inability of the organisms to draw nutrients ormigrate within the semi-solid form of the thixotropic composition toremotely located nutrients results in diminished growth and eventualdeath of the organisms. This aspect of the present disclosure hasparticular significance in those applications wherein the compositionmay be applied via a multi-use applicator. Multiple uses of anapplicator (e.g., nasal applicators) can in some instances expose thecomposition to bacteria. The ability of thixotropic compositionsaccording to the present disclosure to transform from a semi-solid stateto a liquid state, and subsequently return relatively quickly to asemi-solid state makes it very likely that any foreign bacteria willeither be captured and maintained in a particular region of thesemi-solid composition, or exposed only to a limited portion of thecomposition (e.g., the exposed surface within the applicator). As aresult, and because microbial growth and/or mobility are substantiallyimpeded in the composition (e.g., by nutrient starvation), it ispossible to use less (or avoid the need for) preservatives and/oranti-microbials than would be required otherwise. Preliminary testing todate indicates that when a thixotropic composition according to thepresent disclosure is formulated to include a viscosity agent in therange of about 4.0% to no more than 10.0% by weight, microbial growthand/or mobility are substantially impeded.

Some embodiments of the present thixotropic composition may also beformulated to be free of one or more essential microbial growth supportmaterials in amounts that can enable and sustain microbial growthincluding essential elements in the composition of DNA and RNA, as wellas energy supplying nutrients, the latter may vary depending on the typemicroorganism. All bacterial and fungal microorganisms must metabolizesome amount of certain chemicals and nutrients (i.e., the “supportmaterials) to sustain themselves and replicate. Non-limiting examples ofsuch chemicals include phosphorus and nitrogen as they are fundamentalelements of DNA and RNA as well as metabolizable sources of energy suchas glucose and fats or proteins. Thixotropic compositions of the presentdisclosure may be formulated to be free of one or more of the aforesaidchemicals and nutrients necessary for growth in amounts that will enablegrowth and sustain microorganisms. To the extent a thixotropiccomposition includes water, the water may be distilled and/or de-ionizedwater, made isotonic with sodium chloride, and may also be sterilized.In some embodiments, the present disclosure may also include the use ofcontainers and/or pump mechanisms that also are free of the aforesaidchemicals and nutrients in amounts that will sustain microbial growth.The described mechanisms for inhibiting microbial growth may be utilizedin all of the applications described herein.

In nasal applications of a thixotropic composition according to thepresent disclosure, the thixotropic composition may be applied by avariety of different applicators, including a squeeze bottle typeapplicator or a pump type applicator. The act of squeezing the spraybottle or actuating the pump introduces sufficient shear stress into thethixotropic composition to transform the thixotropic composition into aliquid form, which can then be expressed as a spray through a nozzle.The expressed composition in liquid form will be deposited on nasalsurfaces. Once deposited, the thixotropic composition transforms back toa semi-solid form in a matter of seconds. To increase the thickness ofthe deposited layer, the user may utilize multiple sprays of thecomposition. The precise thickness of the applied layer will depend onthe particular thixotropic composition and the number of applications.For example the applied composition layer may be from about a hundredmicrons to several millimeters thick. The spraying of the compositionwill direct the spray to the olfactory area. When sufficient spray isused (which the user may determine), it will coat the nasopharynxthereby and decrease or prevent trigeminal nerve sensed odors or tastes.When subjects have colds or allergies the mucus layer becomes thickerand the sense of smell by be absent or very much decreased. Thisinvention applies a safe and tasteless mucus-like polymer to effecttemporary anosmia or hyposmia.

While the invention has been described with reference to exemplaryembodiments, it will be understood by those skilled in the art thatvarious changes may be made and equivalents may be substituted forelements thereof without departing from the scope of the invention. Inaddition, may modifications may be made to adapt a particular situationor material to the teachings of the invention without departing from theessential scope thereof. Therefore, it is intended that the inventionnot be limited to the particular embodiment(s) disclosed herein as thebest mode contemplated for carrying out this invention.

What is claimed is:
 1. A composition for use in a nasal application,comprising: an aqueous carrier; and a viscosity agent in the range ofabout 4% to about 15% by weight, which viscosity agent is in solutionwith the aqueous carrier; wherein the solution of the aqueous carrierand the viscosity agent is configured as a thixotropic composition. 2.The composition of claim 1 wherein the viscosity agent includesmicrocrystalline cellulose.
 3. The composition of claim 2 wherein theviscosity agent includes sodium carboxymethyl cellulose.
 4. Thecomposition of claim 1, wherein the composition is free ofpreservatives.
 5. The composition of claim 1, wherein the composition isfree of anti-microbials.
 6. The composition of claim 1, wherein thecomposition is substantially free of at least one chemical or nutrientrequired for microbial growth.
 7. The composition of claim 1, whereinthe composition is configured to change from a semi-solid form to aliquid form upon a threshold amount of shear stress being introducedinto the composition, and returning to the semi-solid form upon removalof the shear stress.
 8. The composition of claim 7, wherein in theliquid form the composition is configured to be sprayed as an aerosol.9. The composition of claim 7, wherein in the semi-solid form thecomposition is configured to inhibit microbial organisms from drawingnutrients required for growth through the composition.
 10. Thecomposition of claim 7, wherein in the semi-solid form the compositionis configured to substantially inhibit microbial organism migrationwithin the composition.
 11. The composition of claim 1, wherein thecomposition contains at least one chemical or nutrient required formicrobial growth in an amount less than is necessary to sustainmicrobial growth within or on the composition.
 12. The composition ofclaim 1, wherein the composition is free of chemical or nutrientrequired for microbial growth.
 13. The composition of claim 1, whereinthe composition contains chemicals required for microbial growth in anamount less than is necessary to sustain microbial growth within or onthe composition.